Introduction
Materials and methods
Treatment | Screening | Baseline | Day 1 of cycle | Enda
| |||||||
---|---|---|---|---|---|---|---|---|---|---|---|
−2 days placebo | −1 day moxb
| 1 | 2 | 3 | 4 | 5 | 6 | ≥7 | |||
Sorafenib 400 mg bid | |||||||||||
Cardiovascular evaluations | |||||||||||
LVEF, MUGA scan
| X | X | X | X | |||||||
QT interval, ECG
c,d
| X | Xe
| X | ||||||||
Supine BP/HRc,f
| X | X | X | X | |||||||
Other evaluations | |||||||||||
PK | Xg
| X | X | ||||||||
Safety | X | X | X | X | X | X | X | X | X | ||
Efficacy | X | X | X | X | X |
LVEF measure
QT/QTc interval measure
Blood pressure and heart rate measure
Pharmacokinetic measure
Safety and efficacy measures
Statistical analyses
LVEF analysis
QT/QTc interval analysis
Blood pressure and heart rate analysis
Pharmacokinetic analysis
Safety and efficacy analyses
Results
Patient characteristics
Sorafenib 400 mg bid | |
---|---|
(N = 53) | |
Demographic baseline characteristics
| |
Race, n (%) | |
Caucasian | 48 (91) |
Hispanic | 5 (9) |
Sex, n (%) | |
Female | 21 (40) |
Male | 32 (60) |
Mean age, y (SD) | 56.8 (10.7) |
<65 years, n (%) | 41 (77) |
≥65 years, n (%) | 12 (23) |
Performance status (ECOG), n (%) | |
0 | 17 (32) |
1 | 33 (62) |
2 | 3 (6) |
Cardiovascular risk assessment
| |
Body mass index,a mean (SD) | 26.6 (5.5) |
Obesity, n (%) | 4 (8) |
Diabetes mellitus, n (%) | 5 (9) |
Type 2 diabetes, n (%) | 2 (4) |
Hypercholesterolemia, n (%) | 9 (17) |
Hyperlipidemia, n (%) | 4 (8) |
Baseline disease characteristics
| |
Stage IV/IVb at study entry, n (%) | 53 (100) |
Tumor type, n (%) | |
Renal cell carcinoma | 11 (21) |
Squamous cell carcinoma | 5 (9) |
Papillary carcinoma (thyroid) | 3 (6) |
Duct cell adenocarcinoma | 2 (4) |
Mesothelioma | 2 (4) |
Bone sarcoma | 2 (4) |
Non–small cell lung carcinoma | 2 (4) |
Prostate | 1 (2) |
Other, including unknown primary | 26 (47) |
Cardiovascular medical history, n (%)
| |
Hypertension | 25 (47) |
Tachycardia | 5 (9) |
Myocardial infarction | 3 (6) |
Coronary artery disease | 2 (4) |
Mitral valve prolapse | 2 (4) |
Arrhythmia | 1 (2) |
Congestive heart failure | 1 (2) |
Left atrial dilatation | 1 (2) |
n = 32 | |
---|---|
Baseline cardiovascular characteristics (at estimated t
max
where indicated)
| |
LVEF(%) (primary analysis group), mean (SD) | 64.9 (7.0) |
Systolic BP at t
max,b mm Hg, mean (SD) | 123.5 (23.0) |
Diastolic BP at t
max,b mm Hg, mean (SD) | 68.4 (13.3) |
HR at t
max,b bpm, mean (SD) | 81.0 (16.5) |
n = 31 | |
---|---|
QT/QTc at t
max
,
b
ms, mean (SD)
| |
QT | 378.5 (39.3) |
QTcB | 437.6 (16.4) |
QTcF | 416.5 (20.3) |
LVEF results
LVEF(%) | Sorafenib 400 mg bid | |||
---|---|---|---|---|
n
| Mean (SD) change from baseline |
n
| Mean (SD) change from baseline | |
Day 1 of cycle 3 | Day 1 of cycle 5 | |||
Change from baseline | ||||
Primary analysis population | 31 | −0.8 (8.6) | 24 | −1.2 (7.8) |
Secondary analysis population | 25 | −1.0 (8.5) | 14 | −1.4 (9.4) |
BP/HR | Day 1 of cycle 2 | Day 1 of cycle 5 | ||
---|---|---|---|---|
≥150/90 mm Hg at t
max, n (%) | 31 | 10a (32) | 16 | 2b (13) |
Primary BP/HR analysis (mm Hg/bpm)
| ||||
Change from baseline at t
max
c
| ||||
Supine systolic BP | 31 | 11.7 (19.0) | 16 | 11.1 (11.8) |
Supine diastolic BP | 31 | 11.0 (12.3) | 16 | 11.9 (13.6) |
Supine HR | 30 | −6.6 (10.6) | 13 | −3.3 (7.3) |
Secondary BP/HR analyses (mm Hg/bpm)
| ||||
Change from baseline over timed
| ||||
Supine systolic BP | ||||
Pre-dosee
| 34 | 9.1 (18.9) | 19 | 13.4 (13.9) |
2 h | 35 | 8.2 (19.8) | 19 | 13.3 (18.6) |
4 h | 34 | 11.7 (20.8) | 18 | 11.0 (18.1) |
6 h | 35 | 13.8 (20.4) | 19 | 15.4 (15.7) |
8 h | 34 | 14.8 (20.8) | 19 | 12.4 (15.4) |
12 h | 34 | 15.9 (18.8) | 18 | 12.9 (16.0) |
Supine diastolic BP | ||||
Pre-dosee
| 34 | 7.6 (14.0) | 19 | 11.1 (12.8) |
2 h | 35 | 7.4 (11.5) | 19 | 11.4 (13.1) |
4 h | 34 | 10.8 (11.6) | 18 | 11.8 (13.2) |
6 h | 35 | 11.3 (13.0) | 19 | 13.6 (11.4) |
8 h | 34 | 11.0 (12.4) | 19 | 14.4 (13.5) |
12 h | 34 | 12.2 (9.7) | 18 | 9.1 (12.0) |
Supine HR | ||||
Pre-dosee
| 33 | −4.4 (8.1) | 16 | −2.9 (10.0) |
2 h | 35 | −5.4 (9.2) | 16 | −0.03 (7.1) |
4 h | 34 | −4.0 (8.8) | 16 | 0.1 (9.2) |
6 h | 35 | −6.0 (8.9) | 16 | 0 (8.7) |
8 h | 34 | −4.2 (11.3) | 16 | 0.7 (8.6) |
12 h | 34 | −5.8 (13.3) | 15 | 1.6 (10.0) |
Maximal change from baselinef
| ||||
Supine systolic BP | 35 | 27.7 (18.5) | 19 | 24.8 (14.4) |
Supine diastolic BP | 35 | 19.8 (9.0) | 19 | 22.0 (11.2) |
Supine HR | 35 | 2.9 (8.2) | 16 | 8.3 (6.8) |
Diagnosis | Medical history | Prior cancer treatment | Baseline medications | LVEF measurements | Length of sorafenib treatment |
---|---|---|---|---|---|
Thymic cancer | Lower extremity neuropathy, pain, cough, GERD, nausea | Cisplatin, etoposide, docetaxel, gefitinib, vinorelbine, gemcitabine, pemetrexed, irinotecan | Prochlorperazine, gabapentin, pantoprazole, chlorpheniramine hydrocodone | 72%—Baseline by study-protocol MUGA scan 25%—ECHO scan during hospitalization for PE, with AFl and CHF (+39 days) 60–65%—repeat ECHO scan (+3 days) 58%—Day 1 of cycle 3 by study-protocol MUGA scan | 14 weeks, discontinued due to PD Interruption for 21 days during hospitalization |
RCC | Mitral valve prolapse, depression, fatigue, past smoking history | IFN-α | 73%—Baseline by study-protocol MUGA scan 55.3%—Day 1 of cycle 3, by study-protocol MUGA scan 48%—Repeat MUGA scan (+29 days) 51%—Repeat MUGA scan (+10 days) 49.8%—Day 1 of cycle 5, by study-protocol MUGA scan | 39 weeks, discontinued due to PD Interruption for 8 days as precaution after LVEF decrease | |
RCC | Hypertension, hyperlipidemia, heart attack, herpes zoster, vertigo, breast cancer, constipation, pain, insomnia, carotid artery stenosis, arthritis, fatigue, diarrhea, cough | IFN-α | Prasvastatin, felodipine, stool softener, acetaminophen, ibuprofen, meclizine, cetirizine | 67.5%—Baseline by study-protocol MUGA scan 54.6%—Day 1 of cycle 3 by study-protocol MUGA scan 58.8%—Day 1 of cycle 5 by study-protocol MUGA scan | 27 weeks, discontinued due to grade 3 atrioventricular block |
RCC | Diabetes, hypercalcemia, hyperlipidemia, constipation, fatigue, weight loss, pain, tachycardia, tingling, cough, shortness of breath, nausea, anemia, dizziness, insomnia, hypertension | IL-2 | Hydrocodone, tramadol, acetaminophen, amitriptyline, glipizide, ranitidine, senna, zoledronic acid, lisinopril, erythropoietin | 67%—Baseline study-protocol MUGA scan 42.2%—Day 1 of cycle 3 by study-protocol MUGA scan 50%—Repeat MUGA scan (+16 days) 59%—Post-study MUGA scan (4 days post-study discontinuation) | 16 weeks discontinued due to PD Interruption for 28 days as precaution after LVEF decrease |
QT/QTc interval results
Sorafenib 400 mg bid | ||||
---|---|---|---|---|
Mean (SD) change from baseline | ||||
n
| QT (ms) | QTcB (ms) | QTcF (ms) | |
Day 1 of cycle 2 | ||||
Primary ECG analysis
| ||||
Change from baseline at t
max
a
| 31 | 17.4 (29.3) | 4.2 (19.2) | 9.0 (18.0) |
Secondary ECG analyses
| ||||
Change from baseline over timeb
| ||||
Pre-dosec
| 34 | 12.3 (26.6) | 1.1 (18.3) | 5.2 (18.3) |
2 h | 35 | 10.6 (27.8) | 0.5 (18.0) | 4.2 (17.9) |
4 h | 35 | 10.7 (29.4) | 2.0 (20.2) | 5.2 (19.4) |
6 h | 35 | 13.1 (27.0) | 1.6 (17.3) | 5.7(18.1) |
8 h | 35 | 12.2 (27.3) | 0.2 (16.1) | 4.5 (14.4) |
12 h | 31 | 10.6 (29.6) | 2.9 (17.2) | 5.8 (19.1) |
Maximal change from baselined
| 36 | 32.9 (24.1) | 16.4 (15.3) | 19.8 (14.4) |
Moxifloxacin (positive control)
| ||||
Change from baseline at 2 h post-doseb
| 49 | 5.7 (24.3) | 4.4 (12.9) | 4.9 (13.7) |
Blood pressure and heart rate results
Pharmacokinetic results
Geometric mean (% CV) | Sorafenib 400 mg bid | ||
---|---|---|---|
Day 1 of cycle 2 (n = 17)a
| Day 1 of cycle 5 (n = 17)a
| Ratiob (90% CI) (n = 17)a
| |
Sorafenib | |||
AUC, mg h/L | 42.8 (36.1) | 36.0 (58.2) | 0.84 (0.69–1.02) |
AUCnorm, kg h/L | 7.5 (48.4) | 6.3 (69.8) | |
C
max, mg/L | 5.4 (53.2) | 4.3 (62.1) | 0.79 (0.66–0.94) |
C
max,norm, kg/L | 1.0 (64.9) | 0.8 (72.5) | |
C
trough, mg/L | 4.1 (73.6) | 3.2 (73.8) | 0.78 (0.61–0.99) |
C
trough,norm, kg/L | 0.7 (85.4) | 0.6 (83.8) | |
t
max, h, median (range) | 2.00 (0–12.00) | 2.00 (0–8.05) | |
N-demethyl metabolite (BAY 43-9007) | |||
AUC, mg h/L | 2.0 (59.1) | 1.1 (74.0) | 0.57 (0.41–0.81) |
AUCnorm, kg h/L | 0.4 (62.8) | 0.2 (80.9) | |
C
max, mg/L | 0.2 (73.4) | 0.1 (75.5) | 0.51 (0.38–0.68) |
C
max,norm, kg/L | 0.1 (75.2) | <0.1 (78.2) | |
C
trough, mg/L | 0.2 (82.3) | 0.1 (82.4) | 0.52 (0.38–0.70) |
C
trough, norm, kg/L | <0.1 (85.0) | <0.1 (84.8) | |
t
max, h, median (range) | 1.00 (0–12.00) | 2.00 (0–12.00) | |
N-oxide metabolite (BAY 67-3472) | |||
AUC, mg h/L | 8.5 (58.3) | 5.2 (98.7) | 0.61 (0.41–0.92) |
AUCnorm, kg h/L | 1.4 (59.6) | 0.9 (103.2) | |
C
max, mg/L | 1.0 (66.8) | 0.6 (96.9) | 0.58 (0.41–0.82) |
C
max,norm, kg/L | 0.2 (70.2) | 0.1 (100.7) | |
C
trough, mg/L | 0.8 (81.1) | 0.5 (109.4) | 0.54 (0.36–0.81) |
C
trough, norm, kg/L | 0.1 (85.9) | 0.1 (111.5) | |
t
max, h, median (range) | 1.00 (0–12.00) | 2.00 (0–8.12) | |
N-oxide metabolite of BAY 43-9007 metabolite (BAY 68-7769) | |||
AUC, mg h/L | 2.8 (92.3) | 1.4 (129.3) | 0.50 (0.28–0.89) |
AUCnorm, kg h/L | 0.5 (91.4) | 0.3 (128.1) | |
C
max, mg/L | 0.3 (101.6) | 0.2 (127.2) | 0.47 (0.28–0.80) |
C
max,norm, kg/L | 0.1 (99.6) | <0.1 (123.6) | |
C
trough, mg/L | 0.3 (114.5) | 0.1 (127.8) | 0.49 (0.29–0.83) |
C
trough, norm, kg/L | 0.1 (113.5) | <0.1 (124.7) | |
t
max, h, median (range) | 2.00 (0–12.00) | 2.00 (0–8.05) |
Safety and efficacy results
Number of patients (N = 53) | ||
---|---|---|
All grades n (%) | Grade ≥3 n (%) | |
Any drug-related adverse event | 43 (81) | 16 (30) |
Rash/desquamation | 20 (38) | 3 (6) |
Hand-foot skin reaction | 16 (30) | 6 (11) |
Diarrhea | 15 (28) | 1 (2) |
Alopecia | 13 (25) | 0 (0) |
Pain, extremity—limb | 12 (23) | 0 (0) |
Mucositis | 8 (15) | 1 (2) |
Fatigue | 8 (15) | 1 (2) |
Nausea | 7 (13) | 0 (0) |
Dermatology—other | 7 (13) | 1 (2) |
Sensory neuropathy | 7 (13) | 0 (0) |
Hypertension | 6 (11) | 1 (2) |
Dermal change | 6 (11) | 0 (0) |